The human immunodeficiency virus, or HIV, is a retrovirus of the lentivirus genus which infects humans and is responsible for the acquired immunodeficiency syndrome (AIDS). Although there are antiretroviral treatments for delaying the appearance of AIDS, no vaccine or definitive treatment is available at present.
HIV has an envelope composed in part of the membrane of the infected cell from which it has come and two types of glycoproteins, namely gp120 and gp41. Inside the envelope there is a protein matrix composed of p17 proteins and containing the capsid consisting of p24 proteins and the nucleocapsid consisting of p6 and p7 proteins. The genome of HIV is a single-stranded RNA which is contained in the capsid in the presence of two enzymes, reverse transcriptase p64 required for transcription of the viral RNA into DNA, and integrase p32 required for integration of the viral DNA into the DNA of the infected cell. These two enzymes as well as protease p10, which participates in assembly of the viral particle, are specific to the retroviruses and are therefore the main targets of antiretroviral treatments.
In the last five years, the arsenal of the antiretrovirals has been enriched with nine new molecules and with three new classes of inhibitors. The purpose of the antiretrovirals is to interfere with various mechanisms: on the one hand, the enzymes of HIV required for its replication and on the other hand, the mechanisms by which it enters the cell. The target proteins of these molecules are therefore essentially reverse transcriptase, integrase, protease and the glycoprotein gp41. Among the most recent antiretrovirals, raltegravir, the first representative of the class of integrase inhibitors (INIs), has recently obtained Marketing Authorization. Elvitegravir, the second product of this class, is currently undergoing clinical trials. The results of the various clinical studies that evaluated the use of these two molecules are very encouraging with regard to virological success, tolerance and immunological response. However, as with other antiretrovirals, resistances to INI appear in studies in vitro and in vivo. These resistances are characterized by the selection of mutations on the gene of the integrase of HIV which have an impact on the sensitivity of the virus to the INIs. The mutations found in patients for whom the therapy failed are mainly localized in the central catalytic domain of the enzyme located between amino acids 50 and 212.
The phenomenon of resistance of HIV to antiretrovirals is a major problem in antiretroviral therapy as it leads to a decrease in efficacy of the treatments and an increase in patient mortality.
Earlier work demonstrated the interaction between microRNAs (miRNAs) and viruses. The miRNAs are single-stranded RNAs with a length of about 21 to 24 nucleotides. There are several hundred microRNA genes in the genomes of most multicellular organisms and, to date, about 500 miRNAs have been identified in humans. The miRNAs are post-transcriptional repressors: by pairing with messenger RNAs, they guide their degradation, or repression of their translation into protein. The miRNA genes are transcribed in the form of long precursors called “pri-miRNA”. These precursors are cleaved in the nucleus to an intermediate called “pre-miRNA” by a complex called Microprocessor which is formed in animals by the enzymes Drosha and DGCR8 (Di George Critical Region 8 or Pasha) and in plants by an enzyme of the Dicer family. Pre-miRNA is an RNA with a length of about 70 nucleotides, folded into an imperfect stem-and-loop by base complementarity between the first half and the second half of its sequence. This pre-miRNA is transported from the nucleus to the cytosol by GTP-dependent active transport through interaction with exportin 5. The pre-miRNA is then cleaved in the cytoplasm by an enzyme of the Dicer family to release a small double-stranded RNA called “miRNA”. This double-stranded miRNA then interacts with a protein of the Argonaute family (Ago1 or Ago2) to form the RISC complex (RNA-induced Silencing Complex). This complex of about 160 kDa has been described as being sufficient for the activity of the miRNAs of repression of translation. However, other proteins such as geminin can also be added to the complex. During formation of the RISC complex, the double-stranded miRNA becomes single-stranded and only the strand specific to the target mRNA is conserved. The target mRNA is then loaded within the RISC complex. At this stage, two routes are then possible depending on the composition of the complex. In the case when the complex contains the protein Ago2, the target mRNA will be degraded. If the complex contains the protein Ago1, translation of the target mRNA will be then repressed.
It has already been demonstrated that certain miRNAs of the host cells are capable of targeting viral RNAs and therefore possess an antiviral role or conversely allow the virus to accumulate in the cell. This situation has notably been described for the miRNA hsa-miR-122a specifically expressed in the liver and promoting replication of the RNA of the hepatitis B virus (Chen et al., 2007).